Appendix 1 URS for Isolator and Safety Cabinets
Short Description
report...
Description
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
1 of 31
CPI – NBMC URS – ISOLATOR and SAFETY CABINETS Abstract Centre for Process Innovation (CPI) is setting up the National Biologics Manufacturing Centre (NBMC) in Darlington. This will undertake process development projects for the UK biopharmaceutical industry. Although this will not be a licenced GMP Facility, it will use internationally recognised standards for operation to ensure that the processes and results of experiments are transferable elsewhere. Two types of Isolator and Safety Cabinets are required as follows: Negative pressure Safety Cabinets for operator & environment protection from cytotoxics Postive pressure Isolator for product protection for mimicking final finishing operation This URS defines the performance requirements for both Isolator and Safety Cabinets and will enable the vendor to design, specify, fabricate, install and commission the equipment. Author
Organisation & Responsibility
Andrew Provan
Process Consultant – eXmoor Pharma
Approved By
Organisation & Responsibility
Robert Haugh
Project Manager – eXmoor
Lucy Foley
Project Engineer - CPI
Harvey Branton
Process and Technical Manager-CPI
Jerry Cooper
Project Manager - CPI
Signature
20th Dec 2013
Signature
DOCUMENT HISTORY Version Verification Reason for Issue Issue 1.0 n/a For Client Review 2.0
n/a
Date
Inc client comments – ready for ITT
Date
Date 12th Dec 2013 20th Dec 2013
Client: Project: Title:
3
4
National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
2 of 31
CONTENTS INTRODUCTION................................................................................................................... 3
1.
2
Centre for Process Innovation (CPI)
1.1
Background ................................................................................................................. 3
1.1
Scope and Purpose of this Document ......................................................................... 3
1.2
Definitions .................................................................................................................... 4
1.3
Purpose of the Isolator and Safety Cabinets ............................................................... 4
REGULATORY REQUIREMENTS ......................................................................................... 5 2.1
Design ......................................................................................................................... 5
2.2
Qualification Requirements ......................................................................................... 5
DOCUMENTATION REQUIREMENTS .................................................................................. 7 3.1
Documentation General ............................................................................................... 7
3.2
Documentation Pre-Delivery ........................................................................................ 9
3.3
Documentation Post-Delivery ...................................................................................... 9
GENERAL REQUIREMENTS ................................................................................................. 9 4.1
Design Codes/Standards ............................................................................................. 9
4.2
Mechanical Design ...................................................................................................... 9
4.3
Electrical Design ........................................................................................................ 10
4.4
Site Safety ................................................................................................................. 10
5
LOCATION, UTILITIES AND CONNECTIONS ..................................................................... 11
6
SCOPE OF SUPPLY ............................................................................................................ 11
7
GLOSSARY AND REGULATORY FOCUS .......................................................................... 12 7.3
Health and Safety ...................................................................................................... 12
7.4
Glossary .................................................................................................................... 12
Appendix 1 –Layout of the Isolators 1st Floor Process CPI-NBMC .............................................. 13 Appendix 2 - SPECIFIC REQUIREMENTS ................................................................................. 14 A2.1
Isolator and Safety Cabinets Operation and Performance ........................................ 14
A2.2
Isolator and Safety Cabinets Controls and Instrumentation ...................................... 17
A2.3
Isolator and Safety Cabinets Ancillaries .................................................................... 19
A2.4
Isolator and Safety Cabinets Construction ................................................................ 19
A2.5
Isolator and Safety Cabinets Air Handling Units ........................................................ 22
A2.6
Isolator and Safety Cabinets Sterilisation .................................................................. 23
A2.7
VHP Generator Operation and Performance ............................................................. 25
A2.8
Cleanroom Sterilisation ............................................................................................. 26
A2.9
VHP Generator Controls ............................................................................................ 27
A2.10
VHP Generator Construction ..................................................................................... 29
APPENDIX 3 –3-WAY VALVE OPERATION ............................................................................... 31
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
1.
INTRODUCTION
1.1
Background
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
3 of 31
The Centre for Process Innovation (CPI) is setting up the National Biologics Manufacturing Centre (NBMC) in Darlington UK to support, develop and progress the biopharmaceutical manufacturing industry in the UK. It will be involved in process development, analytical methods, training, new equipment, new technologies, showcasing equipment and technology, funding, advisory support and act as a centre of collaboration and cross fertilisation of ideas in the UK. The NBMC comprises 5,000m² flexible laboratory facility for process, analytical and technology development, small scale production areas for process demonstration and pre-clinical requirements, clean rooms for GMP simulation of process and equipment and flexible, open-plan areas where new facility design concepts can be developed and tested. In addition to the technical facilities, the Centre will provide training and conferencing facilities together with office and meeting spaces. The NBMC will not be a licenced GMP facility, and therefore will not be producing pharmaceutical material for Clinical Trials nor for sale. Therefore none of the equipment nor processes needs to be qualified or validated according to standard practice in the pharmaceutical industry. However it is a requirement that any experiments or process development work is undertaken to internationally recognised standards, so that the processes can be transferred to manufacturing sites, and the experiments and results are reproducible elsewhere. This will employ the same design, specification, installation and commissioning standards as that for a licenced GMP facility. However it will not be qualified (IQ/OQ) but instead will undergo a process of Documented Commissioning (DocCom), and DV, IV, OV and PV (Design, Installation, Operation and Performance Verification). This will employ many of the standards and technique as for Installation Verification (IV) and Operational Verification (OV), but will not be subject to review by regulatory agencies. The building design, construction and commissioning will be undertaken by others on a separate contract, and will include the shell, clean room and laboratory fit out, HVAC, mechanical services, electrical and other services. The process equipment package (of which the Isolator and Safety Cabinets are part of) will be specified and purchased separately by CPI. 1.2 Scope and Purpose of this Document This specification covers the design, manufacture, installation, testing and documentation of the Isolator and Safety Cabinets for the CPI-NBMC Centre. A total of two 4-glove Isolator and Safety Cabinets are required as follows;
1 negative pressure Safety Cabinets for cytotoxic production
1 positive pressure Isolator for final finishing and formulation.
1 vHP mobile generator to sterilise both Isolators/Safety Cabinets and Clean Room
Both Isolator and Safety Cabinets must be designed for automated VHP Sanitisation.
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
4 of 31
Appendix 2 of this User Requirement Specification (URS) contains requirements, which relate to current Good Manufacturing Practice (GMP) and hence will be qualified according to the requirements of Section 2. User requirements in other sections and appendices relate to Good Engineering Practice (GEP) and safety or provide information and so will not be qualified but will become contractual requirements. This URS will provide a basis for: Manufacture of the Isolator and Safety Cabinets by Supplier.
1.3
Definition of performance testing requirements to be undertaken by the Supplier.
Technical basis of contractual arrangements between the Supplier and the Purchaser
Definitions The definitions employed in this document are as follows: Purchaser
Centre for Process Innovation
Project Manager
Jerry Cooper, CPI
Main Contractor
A design and build contractor, to be appointed
Process and GMP Consultant
eXmoor Pharma Concepts, appointed by the Purchaser to carry out process design and oversee GMP compliance and qualification.
Supplier
The designer and manufacturer of the Isolator and Safety Cabinets
Must/Will
The word “must” or “will” denotes that the requirement is mandatory.
Should
The word “should” denotes that the requirement is good practice/highly recommended, but is not mandatory. Where the Supplier does not meet this requirement it must be agreed with the Purchaser.
May
“May” is used where information is provided to assist the Supplier, and no requirement is implied.
The Supplier of the Isolator and Safety Cabinets is required to adhere to the content of this document; any deviations proposed must be clearly identified and justified by the Supplier. Compliance with the agreed contents must be a contractual requirement of the purchase order and any costs associated with meeting the agreed requirements must be included in the purchase price. Not withstanding anything to the contrary in this specification, the Supplier must be responsible for ensuring that the Isolator and Safety Cabinets are “fit for purpose” and in particular for achieving the performance set forth in this specification. 1.4
Purpose of the Isolator and Safety Cabinets
The Isolator and Safety Cabinets each comprise an aseptic process chamber, its loading and unloading devices and any built-in equipment. The Isolator and Safety Cabinets are required to
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
5 of 31
maintain a Grade A micro-environment in which the various ‘open’ processing stages of individual aseptic batches can be carried out and which is continuously particle monitored. The specific User Requirements detailed in Appendix 2 of this document have been derived from the documents stated above The Isolator and Safety Cabinets are to be used for both aseptic and contained bio processing of microbial fermentation, mammalian cell cultures, purification and conjugation. These activities support the development of CPI-NBMC processes and product developmemt for clinical use, however no clinical material will be generated at the CPI-NBMC Centre and therefore any products manufactured within the Isolator and Safety Cabinets will not be used for human application. The VHP necessary to sterilise the Isolator and Safety Cabinets will be generated by an individual mobile VHP Generator system. The processes to be carried out in the Isolator and Safety Cabinets are manual, may be repetitive and may involve frequent material transfers in and out of the Isolator and Safety Cabinets, thus ergonomics is a major design factor. Hydrogen Peroxide Vapour (VHP) is hazardous to health, so the Isolator and Safety Cabinets must incorporate appropriate safeguards for CPI-NBMC, maintenance and engineering personnel.
2
REGULATORY REQUIREMENTS
2.1
Design
2.1.1.
The Isolator and Safety Cabinets will be used in a GMP-like environment, therefore, design, construction and installation does not have to comply with current Good Manufacturing Practice, as referenced in Section 7, but should try to meet requirements where possible.
2.1.2.
The Isolator and Safety Cabinets must be designed, tested, supplied and commissioned in accordance with a documented quality assurance system implemented by the Supplier
2.2
Qualification Requirements
2.2.1.
All qualification activities must conform to the requirements set out in the Facility and Equipment Verification Plan, ####
2.2.2.
The Isolator and Safety Cabinets have been assessed as ‘Direct Impact’ systems requiring the following qualification stages. This qualification is required even though the unit does not have to comply with cGMP because the gassing cycle development will not be able to be completed without the unit being verified. Functional Design Specification (FDS)
Design Verification (DV) including Verifictaion Traceability Matrix (VTM)
Factory Acceptance Test (FAT)
Commissioning
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
Installation Verification (IV)
Operational Verification (OV)
Gassing Cycle Development (GCD)
Performance Verification (PV)
2.0
Page:
6 of 31
2.2.3.
To support qualification the Supplier must provide a cross reference matrix (Verification Traceability Matrix (VTM)) between this URS document, the Functional Design Specification and specific tests to be carried out during Installation and Operational Qualification. Appendix 2 is set out in the format of the VTM.
2.2.4.
The qualification process will follow the principles set out in the ISPE Baseline Guide Vol. 5, Commissioning and Qualification.
2.2.5.
All Supplier testing of critical items will be carried out following pre-approved protocols and test sheets and witnessed by the Purchaser.
2.2.6.
The Supplier is responsible for providing all necessary documentation. Where test sheets need to be completed, the Supplier must follow pre-approved documentation procedures, according to pharmaceutical industry standards and take responsibility for the correct completion of the test sheets, follow up actions and close-out of the testing
2.2.7.
The Supplier must, at the DV/VTM stage, complete a copy of the matrix given in Appendix 2 in the following way. Where “Required” is entered in the DV row, the Supplier must replace this with a statement which confirms design compliance or not with the URS and gives a documentary reference to the Suppliers Functional Design Specification which relates to the subject. Where “Required” is entered in the IV row, the Supplier must replace this with a test reference from their IV protocol. Where “Required” is entered in the OV row, the Supplier must replace this with a test reference from their OV protocol. Where N.A. is entered in any row, this may be ignored. Note: Appendix 2 is set out to be printed and used as A3 landscape.
2.2.8.
The following table summarises the responsibilities for Supplier qualification services.
Responsibilities for Qualification Prepare Protocol
Approve Protocol
Execute Protocol
Write Report Approve Report
FDS
Supplier
Approval by Purchaser is integral with DV
n.a.
n.a.
n.a.
DV (inc. VTM)
Supplier
Purchaser
Supplier & Purchaser
Supplier
Purchaser
FAT (i)
Supplier
Purchaser
Supplier. Purchaser to witness
Supplier
Purchaser
Commissioning
Supplier
Supplier
Supplier.
Supplier
Purchaser
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
7 of 31
Purchaser to witness
(i) IV
Supplier
Purchaser
Supplier. Purchaser to witness
Supplier
Purchaser
OV
Supplier
Purchaser
Supplier. Purchaser to witness
Supplier
Purchaser
GCD
Supplier
Purchaser
Supplier. Purchaser to witness
Supplier
Purchaser
PV
Purchaser (Supplier to advise)
Purchaser
Purchaser (Supplier to advise)
Purchaser
Purchaser
(i)
Correctly documented FAT and / or Commissioning results may be leveraged into IV and OV by agreement, if FAT and commissioning is undertaken to pre-approved Procedures and included in the Supplier’s Quality Assurance System
3
DOCUMENTATION REQUIREMENTS
3.1
Documentation General
3.1.1.
All documentation, including software printouts, must be in English.
3.1.2.
Documentation must meet, as a minimum, the following requirements: Providing all the details necessary so that the Isolator and Safety Cabinets can be qualified Providing ‘as built’ records and drawings. Providing information so that operating and maintenance procedures can be prepared.
3.1.3.
Plant items must be uniquely identified on schematic diagrams.
3.1.4.
All documentation must be identifiable by the Purchaser item number, which is ZNNN. All validation documentation must be numbered as follows: NBMC.ZNNN.Vnn.XX, where nn = version number and XX = document type (FD = Functional Design Specification, DV = Design Qualification, IV = Installation Qualification, OV = Operational Qualification etc.)
3.1.5.
The final issue by the Supplier of any piece of documentation is to be marked and certified as the “As-built” or “As installed” version. The “As-built” and “As-installed” document is defined as the document which accurately represents the system at Handover, having passed through FAT, DV, Commissioning, IV and OV with all documentation discrepancies cleared and final data verified.
3.1.6.
The supplier must provide one paper copy and one digital copy of the Operation and Maintenance Manual relevant to the specific Isolator and Safety Cabinets. (Copies of a generic manual covering numerous models are not permitted).
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
8 of 31
The supplier must provide one paper copy and one digital copy of all other documentation relevant to the specific Isolator and Safety Cabinets, as listed below. Digital copies must be delivered on CDROM, DVD or read-only USB Flash-Drive and must be recoded in industry standard software packages such as Microsoft Office, Adobe pdf and AutoCad for drawings.
Client: Project: Title:
3.2
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
9 of 31
Documentation Pre-Delivery
3.2.1.
Functional Design Specification (FDS), machinery and controls.
3.2.2.
General arrangement drawings and schematics
3.2.3.
Parts list with component specifications
3.2.4.
Material certificates for all product contact parts or certificates of conformity to the specification for all parts not provided with individual material certificates or other quality assurance documents
3.2.5.
Control schematics with control panel layouts and wiring diagrams
3.2.6.
Instrumentation list with calibration certificates for critical instruments
3.2.7.
Operating and Maintenance manuals
3.2.8.
Preventative maintenance schedule and recommended spares list for 2 years
3.2.9.
Executed FAT protocol and qualification protocols for approval, as noted in Section 2
3.2.10. Commissioning Procedure for comment and approval prior to execution 3.2.11. Qualification protocols for approval, as noted in Section 2
3.3
Documentation Post-Delivery
3.3.1.
Any documentation which was issued as “preliminary”, “draft” or “for construction” or any other documentation which requires revision as a result of commissioning and qualification must be certified “As Installed” and re-issued.
3.3.2.
Executed Commissioning Procedure approved by the Purchaser with a list of commissioning spares replaced.
3.3.3.
Calibration certificates for all test equipment used at any stage.
3.3.4.
Executed qualification protocols and qualification reports for approval, as noted in Section 2.
4
GENERAL REQUIREMENTS
4.1
Design Codes/Standards
4.1.1.
The Isolator and Safety Cabinets must be permanently CE Marked to confirm compliance with all relevant EU Directives, and a suitable conformance certificate must be provided.
4.1.2.
The Isolator and Safety Cabinets s must be safe to operate and comply with the Provision & Use of Work Equipment Regulations, 1998.
4.2 4.2.1.
Mechanical Design The Isolator and Safety Cabinets must be designed as a complete, stand alone, unit comprising process chamber, transfer hatch, air handling units (complete with fans and
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
10 of 31
HEPA filters), VHP connections, controls (with intuitive HMI), powered height adjustment, sleeves and gloves. 4.2.2.
The Isolator and Safety Cabinets must be ergonomically designed to allow ease of use, cleaning and maintenance.
4.2.3.
Sensing devices must be easily accessible and removable for calibration and maintenance purposes.
4.2.4.
Supplier to confirm automated valves are equipped with open/closed limit switches as standard.
4.2.5.
The Isolator and Safety Cabinets must have adequate temporary protection suitable for transporting to site and for on site storage and protection once installed up to and including the commissioning stage.
4.3
Electrical Design
4.3.1.
All electrical equipment, documentation and installation must comply with all local regulations in the UK (the current edition of BS7671, IEE Wiring Regulations) and EN60204 Safety of Machinery.
4.3.2.
Electrical equipment must only be connected to a single source of supply. The machine must be equipped with an isolation switch that completely isolates the machine from the mains electricity supply. Any other voltages and frequencies must be produced from within the equipment. Power supply for instrumentation and control must be 24V DC.
4.3.3.
All electrical components and connectors must be compatible with those used in the UK
4.3.4.
All electrical components must be contained in protective enclosures, having Ingress Protection suitable for cleanroom which are frequently cleaned with lIVuid products and also sterilised with VHP.
4.3.5.
Access to electrical enclosures must only be permitted by use of a key or tools. Panel doors must be interlocked to disconnect power from exposed equipment when the door is opened. It is permissible to allow low voltage (24V) circuits to remain powered when the door is open if mains voltage equipment is strictly segregated and effectively protected from accidental contact.
4.3.6.
All Isolator and Safety Cabinets metalwork must be securely earthed and an earth continuity test carried out.
4.3.7.
Adequate short circuit protection must be installed to guard against failure of individual electrical circuits.
4.3.8.
Clear labelling must be fitted to each fixed component and termination, labelling must correspond to that used on wiring diagrams and parts lists.
4.3.9.
An Electrical Safety Test must be carried out and documented to confirm safe installation.
4.4 4.4.1
Site Safety Where any site work (offloading, unpacking, moving into position, re-assembly, installation, connection to services, cleaning, commissioning, testing, calibrating etc.) is to be carried out by the Supplier, this will be under the direct control of the Main Contractor, although the Purchaser may inspect or witness the work. The Site Rules of
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
11 of 31
the Main Contractor and GSTT must be followed and Risk Assessments and Method Statements for the work must be submitted and approved before starting work. All Supplier’s staff working on site will be required to undergo Site Induction by the Main Contractor.
5
LOCATION, UTILITIES AND CONNECTIONS
5.1.
The Isolator and Safety Cabinets will be located in the following location at CPI-NBMC; Negative contained Safety Cabinets – Cytotoxic laboratory – Room 1.20 Positive pressure Isolator – GMP Simulation – Room 1.33 or Room 1.34
5.2.
The Isolator and Safety Cabinets will be floor standing, the ceiling is 2700 mm above FFL.
5.3.
The room temperature is controlled at 20 ± 3 oC and humidity will not be controlled
5.4.
The route from the goods unloading area is via a goods lift and internal corridors constrained by doors with an effective opening of 1800 mm wide and 2500 mm high, with restricted turning space.
5.5.
Utility
Parameters
Connection
Power
13 A, 230 V, 1 Phase, 50Hz
13A UK type socket
CO2 Vacuum
2 bar Hospital vacuum
0.5 inch quick connect 0.5 inch quick connect
6
SCOPE OF SUPPLY
6.1.
The scope of supply must comprise. Detailed design, manufacture, installation, commissioning and qualification of the Isolator and Safety Cabinets
6.2.
Packing and delivery to site, including insurances and customs duties etc. Offloading, unpacking and moving into position.
6.3.
Re-assembly and installation, including connection to services, which will terminate approximately 2m away from the machines.
6.4.
Commissioning including supply of all consumables, spare parts, labour and calibrated test equipment used in the tests. Note that commissioning and qualification may be scheduled several weeks after installation.
6.5.
Qualification services listed in Section 2
6.6.
Comprehensive training in both operation and maintenance, with Training Certificates issued to Purchaser’s staff who have completed the course.
6.7.
Documentation, as listed in Section 3.
6.8.
Handover will be achieved when a Handover Certificate (prepared by the Supplier) is signed by the Purchaser. The Handover Certificate will confirm the completion of the following: Equipment is installed, commissioned and operating without snags or faults O & M Manual has been delivered and its content approved
Centre for Process Innovation (CPI)
Client:
National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Project: Title:
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
12 of 31
DV, IV and OV protocols have been executed and unconditionally approved GCD has been completed and unconditionally approved Training has been completed and training certificates issued All other documentation listed in Section 3 has been delivered Spare parts ordered with the contract have been delivered
6.9.
Minimum 12 months Warranty from date of Handover, covering on-site repair and replacement of defective parts with re-qualification, if necessary 48 hour maximum response time required.
6.10.
One year’s on-site planned maintenance contract, with defined rates for labour and parts. Tenderer to provide an option to extend the planned maintenance contract, including a 48 hour maximum response time breakdown service, for years 2 to 3.
6.11.
Supplier must provide a minimum of 1 spare HEPA filter for each model number of filter used in the Isolator and Safety Cabinets. For example should an Isolator or Safety Cabinets use 1 off 300 x 300mm H14 and 1 off 600 x 600mm H14 and there are 6 Isolator and Safety Cabinets all the same then commissioning consumables must be 6 off 300 x 300mm H14 and 6 off 600 x 600mm H14. The commissioning spares are to be shipped with the equipment and identified as an individual line item for costing purposes.
7
GLOSSARY AND REGULATORY FOCUS
7.3
Health and Safety o
Control of Substances Hazardous to Health (COSHH) Regulations Schedule 3 2002
o
Genetically Modified Organisms (Contained Use) Regulations 2000 (GMO(CU))
o
Genetically Modified Organisms (Contained Use) (Amendment) Regulations 2002
o
Advisory Committee on Dangerous Pathogens (ACDP) Approved List of Biological Agents 2004
o
Pressure Systems Safety Regulations 2000
7.4
Glossary o
BMS – Building Management System
o
EMS - Environmental Monitoring System
o
HMI – Human-Machine Interface
o
N.A. – Not applicable
o
TBA – To be advised or to be agreed
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
13 of 31
Appendix 1 –Layout of the Isolators 1st Floor Process CPI-NBMC
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
14 of 31
Appendix 2 - SPECIFIC REQUIREMENTS A2.1
Isolator and Safety Cabinets Operation and Performance Requirement
A2.1.1.
The Isolator and Safety Cabinets must accommodate the following ‘generic’ process steps (Note that specific loads and operations will be defined by individual processes and the two typical loads, identified by the batch sequence diagrams, will be used to inform VHP gas cycle development): a) Preparation Manual cleaning Glove testing Assemble racking and fixed equipment parts, as necessary. b) Loading Load stock boxes of disposable items Load initial single-use disposable tubing sets’or well-plates or centrifuge tubes or transfer bags or culture flasks Load ‘tools’ and static equipment (eg battery powered balance, tube welder) to be used in the process c) Pre-Process VHP Cycle Sterilisation of all internal surfaces and items placed inside the Isolator and Safety Cabinets d) Transfers Load extra equipment items via Transfer Hatch Load extra WFI, media and buffer solutions via Transfer Hatch Introduce blood-bag, cell culture bag, tube or culture flask containing cells e) Processing Carry out process manipulations Remove disposable tubing sets via Transfer Hatch. Remove wastes via Transfer Hatch. Return tubing sets via Transfer Hatch. Introduce new reagents and disposable equipment via the Transfer Hatch f) Processing and Transfers Steps (d) – (e) may be repeated several times, with subtle variations g) Remove Final ‘Product’ Remove final ‘product’ bag or cryo-vial via Transfer Hatch h) Open, Clean and Tidy (Note: If viral vectors have been used, it will be necessary to run a VHP sterilisation cycle before opening) Remove wastes Manually clean
Fulfilment DV
Required
IV
To be demonstrated at Mock-up stage
OV
N.A.
Sign / Date
Client: Project: Title:
A2.1.2.
A2.1.3.
A2.1.4.
A2.1.5.
A2.1.6.
A2.1.7.
A2.1.8.
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
15 of 31
DV
Required
IV
To be demonstrated at Mock-up stage
OV
N.A.
It must be possible to move in or out all the removable items either via the front opening window (prior to or after a process batch) or via the Transfer Hatch (during a process batch). It must be possible to fully open the Isolator and Safety Cabinets window to the same internal width and height of Isolator and Safety Cabinets chamber to manually clean inside and to clean and maintain any built-in equipment.
DV
Required
IV
To be demonstrated at Mock-up stage
OV
N.A.
In order to satisfy A2.1.1 and A2.1.2 it is likely that the ‘working area’ (that which is accessible to the operator using the glove-ports) of the Isolator and Safety Cabinets may be approximately 2000 mm x 600 mm. The working area must be supplemented with a perorated storage shelf, 70 mm wide mounted on the ‘back’ wall of the Isolator and Safety Cabinets and a ‘x-y-hanging rail grid with hooks for sterile bags etc.
DV
Required
IV
Required
OV
N.A.
10” gloveports must be sited to suit the process with optimum ergonomics.
DV
Required
IV
To be demonstrated at Mock-up stage
OV
N.A.
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
The ‘working area’ (that which is accessible to the operator using the glove-ports) must accommodate the following removable items, whilst leaving adequate space to work Blood bags, tubing sets, product and buffer bags Wastes (discard) container (200 mm dia.) Bottles or bags of media (1 to 5 L) 1 No. Centrifuge racks for 25 mm tubes (150 mm x 80 mm) 2 L container (130 mm dia.) 2 No. Gilsons-type pipettes in rack (300 mm x 100 mm) 2 No. Pipette tip boxes (80 mm x 80 mm) Sharps container (100 mm x 100 mm) Syringe and needles Sample containers Packs of dry or wet wipes and other minor consumables Tube welder Settle plates
An Isolator and Safety Cabinets must maintain a Grade A environment at all times during a production run, which may last several days.
A downward vertical unidirectional velocity of 0.45 + 20 % m/s must be maintained at the expected level of open processing, which is understood to be an area approximately 100 mm off the internal walls and approximately 300 mm off the base (to be qualified with the Isolator and Safety Cabinets empty).
The equivalent air flow rate in the Isolator and Safety Cabinets must be at least 500 air changes per hour.
Client: Project: Title:
A2.1.9.
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
16 of 31
It must be possible to sterilise, with VHP, the Isolator and Safety Cabinets, its equipment and full load of disposable items using a cycle of approximately 90 minutes duration, and ideally as short as possible. “Sterilisation” is defined in Section A2.6. For clarification of the time, the 90 mins refers to the time from initiating the VHP cycle on the generator until aeration is completed i.e. H2O2 is below 1ppm. This 90 mins will include the initial gassing, dew point, dwell time and aeration.
A2.1.10. It must be possible to sterilise items placed in the Transfer Hatch either by a ‘short’ VHP cycle (less than 60 minutes in total) or by manual wiping down or by ethanol spraying.
A2.1.11. The lighting level in the Isolator and Safety Cabinets must not be less than 600 lux at the ‘working area’ level.
A2.1.12. When in ‘production’ mode the Isolator chamber must be maintained at a pressure at least 25 Pa higher than that of the Transfer Hatch and the Transfer Hatch must be maintained at a pressure at least 50 Pa higher surrounding room. This applies to the Isolators; GMP Simulation in 1.20
OV
Required
DV
Required
IV
N.A.
OV
Required + Gas Cycle Development
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
N.A.
OV
Required
A2.1.13. When in ‘production’ mode the Safety Cabinets chamber must be maintained at a pressure at least 200 Pa lower than that of the Transfer Hatch and the Transfer Hatch must be maintained at a pressure at least 50 Pa higher surrounding room. This applies to the negative pressure safety cabinets; Cytoxics in 1.20 A2.1.14. The temperature in the Isolator and Safety Cabinets chamber must not be more than 4 °C above the surrounding room temperature when in ‘production’ mode.
A2.1.15. The positive pressure Isolators must pass a leak test. The test criterion is a pressure decay of less than 25 Pa in 1.5 minutes when the pressure is raised to +250 Pa with the Isolators sealed. {This represents ≤1% volume loss per hour as per Isolator Class 3, ISO 10648-2 and ISO 14644-7 draft}. A2.1.16. The negative ressure Safety Cabinet must pass a leak test. The test criterion is a pressure decay of less than 25 Pa in 1.5 minutes when the pressure is lowered to -250 Pa with the Isolator and Safety Cabinets sealed. {This represents ≤1% volume loss per hour as per Isolator Class 3, ISO 10648-2 and ISO 14644-7 draft}. A2.1.17. The noise from the Isolator and Safety Cabinets in operation must be no more than 65dB at 1m away.
Client: Project: Title:
A2.2
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
17 of 31
Isolator and Safety Cabinets Controls and Instrumentation Requirement (applies to all Isolator and Safety Cabinets unless indicated)
A2.2.1.
A2.2.2.
A2.2.3.
A2.2.4.
A2.2.5.
Fulfilment
The Isolator and Safety Cabinets control panel (HMI) must indicate: Isolator and Safety Cabinets and Hatch Pressures (digital) Air Flowrate or Velocity in the Isolator and Safety Cabinets, annotated in Air Changes per Hour or m/s. Terminal and exhaust HEPA filter pressure-drops (Magnahelic or digital). Gassing cycle status Hatch door status Alarms
DV
Required
IV
Required
OV
Required
DV
Required
IV
Required
OV
N.A.
Settable high and low alarms must be fitted for Pressure (independent chamber and hatch) Flow/velocity Seal failures Alarms must be annunciated by audible and visible means. Alarms must be latched, ie. alarms can only be cleared by manual intervention once the excursion has been corrected. Additionally, the Isolator and Safety Cabinets must receive, display and annunciate a common VHP Generator alarm and a particle counter. Alarm noise to be noticeable, but not with a disturbing or distracting intonation or volume.,
DV
Required
IV
Required
OV
Required
The control system must log all alarms (alarm type, time of alarm, time acknowledged and time cleared) and retain these for operator information at the end of a batch. These alarms are independent of any EMS alarms.
DV
Required
IV
Required
OV
Required
DV
Required
IV
Required
OV
N.A.
The HMI requirements of the built-in equipment have been listed in A2.3. These controls should be incorporated in the same panel as the Isolator and Safety Cabinets controls, if this is not possible, they must be mounted closeby.
The required range and accuracy of the instrumentation is given in the table below. Instrument
Range
Accuracy
Precision
Air Flow
0 – 900 Ach/h
+ 5 Ach/h
5 Ach/h
Air Velocity
0 – 10 m/s
+ 0.1 m/s
0.1 m/s
Pressure
-300 to +600 Pa
+ 5 Pa
10 Pa
HEPA filter DP
0 – 500 Pa
+ 5 Pa
10 Pa
Hydrogen Peroxide Conc. (low)
0 – 10 ppm
+ 0.5 ppm
0.5 ppm
Sign / Date
Client: Project: Title:
A2.2.6.
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
18 of 31
The Isolator and Safety Cabinets control system must monitor an ‘extract healthy’ signal either from the BMS or directly and display and annunciate it. Furthermore, the Isolator and Safety Cabinets control system must not allow a VHP cycle to start if this signal is not present and it must go into a ‘safe-hold’ state if the signal drops out during the aeration phase of a gassing cycle.
DV
Required
IV
Required
OV
Required
The control system must manage and report automatic leak tests: leak test on demand A pre-gassing leak test as part of the VHP sterilisation cycle Glove leak test. The Isolator and Safety Cabinets must be supplied with a glove leak-test device for semi-automatic operation.
DV
Required
IV
N.A.
OV
Required
Control systems must be protected from power failure by a dedicated UPS with capacity for 30 minutes operation. UPS to be alarmed for failure or low battery. The UPS must also include power surge protection. The Isolator and Safety Cabinets will be connected to a ‘maintained’ supply, therefore power interruptions are anticipated to be momentary. In the event of power failure, the Isolator and Safety Cabinets must restart automatically to its previous set point, with no operator intervention.
DV
Required
IV
Required
OV
Required
The inner door of the Transfer Hatch must be controlled so that a variable delay is applied after the outer door is closed until the inner door may be opened. This is to allow alcohol vapour to be swept away and Grade A conditions to re-establish.
DV
Required
IV
N.A.
OV
Required
A2.2.10. The control system must be password protected, with at least three levels of entry (Operator, Supervisor and Engineer). If the selected control system falls within the guidance of Annex 11 (Computerised Systems) of the EU GMP regulations, then password protection must comply with sections 8 and 10 of Annex 11 of the EU GMP regulations. This states that all actions carried out under password control must be logged, with the identity of the person initiating the actions.
DV
Required
IV
N.A.
OV
Required
A2.2.11. All instruments must be clearly labelled in English with their function.
DV
Required
IV
Required
OV
N.A.
A2.2.7.
A2.2.8.
A2.2.9.
Client: Project: Title:
A2.3
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
19 of 31
Isolator and Safety Cabinets Ancillaries Requirement (applies to all Isolator and Safety Cabinets unless specifically noted)
Fulfilment
Sign / Date
Fulfilment
Sign / Date
The Isolator and Safety Cabinets must incorporate a built in peltier-type cold/heat block. A2.3.2
A2.4
The cold block must be sealed into the base plate of the Isolator and Safety Cabinets. The cold block must have a cover that is flush with the base of the Isolator and Safety Cabinets, with a removable magnetic handle in order to maximise the working area in the Isolator and Safety Cabinets when the cold/hot block is not being accessed. The cold block must be 30cm x 20cm x 20 cm. The cold hot block must be able to maintain temperatures between -20° C to 37° C. The cold block must be supplied filled with proprietary heat transfer beads. Isolator and Safety Cabinets Construction Requirement (applies to all Isolator and Safety Cabinets unless specifically noted)
A2.4.1.
A2.4.2.
A2.4.3.
A2.4.4.
A2.4.5.
A2.4.6.
The CPI-NBMCIsolator and Safety Cabinets configuration comprises the Isolator and Safety Cabinets chamber and a Transfer Hatch at the right-hand end.
DV
Required
IV
Required
OV
N.A.
The overall external dimensions of the Isolator and Safety Cabinets, should not exceed 2400 mm (w) x 1200 mm (D)x 2100 mm high. Note should also be made of the access route limitations shown on the layouts in Appendix 1; Equipment lift – 2.4m wide, 3.4 long, 2.5m high (to be confirmed) Corridors on process floor – 2.5m wide Doors into process rooms – 1.8m wide
DV
Required
IV
Required
OV
N.A.
The internal surfaces of the Isolator and Safety Cabinets must be constructed in 316L stainless steel (minimum thickness 3mm).
DV
Required
IV
Required
OV
N.A.
All internal surfaces must be finished smooth and crevice free. “Folded” metal construction is not permitted, joints must be welded, with the welds ground smooth and polished to match the base metal sheet. Internal corners must be radiused (at least 20mm recommended). Internal finish < 0.8 micron Ra. External finish < 1.8 micron Ra.
DV
Required
IV
Required
OV
N.A.
The internal height of the Isolator and Safety Cabinets must be approximately 800 mm.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
The Isolator and Safety Cabinets base plate height must be approximately 900 mm above floor level, with ±150 mm powered adjustment.
Client: Project: Title:
A2.4.7.
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
20 of 31
The Isolator and Safety Cabinets chamber must be equipped with 2 No. power sockets (5 A rating) for removable equipment. These should be covered power sockets that will need to be opened during VHP gassing. The location of the sockets should not interfere with the operation inside the Isolator and Safety Cabinets. The Isolator and Safety Cabinets chamber must be equipped with 2 No. USB bulkhead sockets. One to be type A on the inside and type B outside and the other vice versa. Power and data sockets provided in the Isolator and Safety Cabinets must be sealed, allowing no leakage path for air into/from the Isolator and Safety Cabinets chamber.
DV
Required
IV
Required
OV
N.A.
The Isolator and Safety Cabinets must be equipped with at least one permanently installed particle sampling point (isokinetic nozzle) for connection to a particle counter at working height (300mm) in a position that doesn’t interfere with the processing. The head must be connected with “Bev-a-Line” tubing to the particle counting head which must be mounted on the Isolator and Safety Cabinets. The particle counter should be positioned inside the Isolator and Safety Cabinets cladding, and be accessed by a removable panel, Note: Isokinetic nozzle and Bev-a-Line tubing to be supplied and installed by Isolator and Safety Cabinets Supplier, particle counting head to be supplied by the EMS Supplier. Bev-a-line must be installed to the manufacturers recommendations. The tubing must be positioned and maintained without any kinks to ensure particles cannot get trapped inside.
DV
Required
IV
Required
OV
N.A.
The Isolator and Safety Cabinets must be equipped with at least one sealable port for the introduction of a low concentration H2O2 sensor. (Sensor will be included in the VHP Generator scope of supply).
DV
Required
IV
Required
OV
N.A.
A2.4.10. The clear aperture of the door between the Transfer Hatch and the Isolator and Safety Cabinets chamber must not be less than 400 mm x 400 mm. Likewise the outer door of the Transfer Hatch should be a matching size. The inner and outer doors of the Transfer Hatch must be interlocked, so that only one door can be open at any time. This interlock may be inactivated when the Isolator and Safety Cabinets is open for cleaning or maintenance.
DV
Required
IV
Required
OV
N.A.
A2.4.11. It is intended that the Isolator and Safety Cabinets be installed against the wall of the cleanroom and therefore operational or maintenance access will not be available from the rear of the Isolator and Safety Cabinets. Supplier must confirm that this is acceptable or suggest alternatives. For example the Isolator and Safety Cabinets may be on rollers to allow for access for cleaning or maintenance.
DV
Required
IV
Required
OV
N.A.
A2.4.12. The support frame must be rigid, fabricated from stainless steel or white powder-coated steel and mounted on height adjustable cleanroom-type feet. The support frame must be within the footprint of the main body of the Isolator and Safety Cabinets and allow for wall to floor coving in the room. The support frame must be designed so that operators of different statures can work at the gloveports; exact details and specification of any height adjusting devices necessary to be agreed during ergonomic trials.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
A2.4.14. Doors and windows must be constructed in laminated safety glass or clear cast acrylic, with 316 L stainless steel frames. Doors and windows must be interlocked (Isolator and Safety Cabinets can’t run in “production” or “gassing” mode if the outer doors or windows are open or not locked). Windows may slope back for operator comfort
DV
Required
IV
Required
OV
N.A.
A2.4.15. Windows must be interlocked (Isolator and Safety Cabinets can’t run in “production” or “gassing” mode if the
DV
Required
A2.4.8.
A2.4.9.
A2.4.13. The enclosure for the fan/filter unit and controls must be fabricated from polished stainless steel or white powder coated steel.
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
21 of 31
windows are open or not locked). Windows must be safely self-supported when open.
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
A2.4.17. If mechanical devices are used to secure door and window seals, lockable over-centre latches are preferred, screw-down closure devices are not acceptable. The holding hook for the transfer hatch door should be angled up so that the door can not fall off when suspended.
DV
Required
IV
Required
OV
N.A.
A2.4.18. Seals for doors and windows must be fabricated using pharmaceutical industry approved elastomers, including silicone rubber, PTFE, EPDM and viton, which must be VHP resistant.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
Required
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
A2.4.16. Opening windows and doors must be sealed with retained inflatable or vacuum seals. A 0.22 μm filter must be installed to filter the compressed air which is used for the inflatable seals. Vacuum seals must be protected with non-return valves to maintain vacuum in the event of pump failure. Seal pressures must be continuously monitored, when operational, with a local alarm.
A2.4.19. Four glove-ports (10 inch port diameter) must be equally spaced, low, in the Isolator and Safety Cabinets to suit the process with optimum ergonomics.
A2.4.20. Gloveport sleeves must fit securely onto the shoulder rings (double O-rings preferred) and must be easy to change when required.
A2.4.21. Gloveport sleeves must be tough but flexible and resistant to the effects of VHP. They must be of the double-layer type, self-indicating of leakage.
A2.4.22. The cuff assembly must allow for safe change of the gloves, without breaking sterility or containment.
A2.4.23. Gloves are considered consumable but the Isolator and Safety Cabinets supplier must provide gloves sufficient for commissioning and validation. Gloves may be recommended by the supplier, but these must be of material resistant to VHP, available in various sizes, non-allergenic and widely available. A2.4.24. All internal surfaces and fittings inside the Isolator and Safety Cabinets must be compatible with VHP sterilisation and manual cleaning with proprietary cleaning products (75% IMS), Shield Medicare biocides X, Klercide A, B & C. Virkon and Chlorsept disinfectant tablets may be used inside of the Isolator and Safety Cabinets. Use of these tablets within the Isolator and Safety Cabinets will be limited and the surface will be cleaned with water following contact and subsequent sterilisation. All external surfaces of the Isolator and Safety Cabinets must be compatible with VHP sterilisation of the room in which it is located and manual cleaning with the same range of cleaning products as used inside. There must be space allowance for a tool for cleaning of far walls and sides of the Isolator and Safety Cabinets. The casters and some of the external surfaces of the Isolator and Safety Cabinets must be compatible sporicides including Sporklenz, Clearklens Bi Spore.
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
22 of 31
A2.4.25. The Isolator and Safety Cabinets must be identified with a permanently fixed “tag”, the tag having an engraved number corresponding to its identification
A2.4.26. All the documentation listed in Section 3 of this URS must be delivered with the Isolator and Safety Cabinets.
A2.4.27. There must be a sealable port to allow a peristaltic pump tubing (diameter of tubing to determined) to be inserted into the Isolator and Safety Cabinets (before VHP gassing) to allow a peristaltic and/or vacuum pump to be kept outside the Isolator and Safety Cabinets, and pump/remove fluid into/out of the Isolator and Safety Cabinets. A2.4.28. A non-slip bar to act as a foot rest will be fitted to allow the operator to sit down in an ergonomic manner when using the Isolator and Safety Cabinets. Foot switches to be provided for: Inner hatch door open/close Centrifuge stop/start
A2.5
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
Required
DV
Required
IV
Required
OV
Required
Isolator and Safety Cabinets Air Handling Units Requirement
A2.5.1.
A2.5.2.
A2.5.3.
A2.5.4.
The Isolator and Safety Cabinets chamber and Transfer Hatch must re-circulate air internally, but must use conditioned air from the room for pressure and temperature control purposes.
Fulfilment DV
Required
IV
Required
OV
N.A.
When in operation, it is expected that a constant volume of air, 120 +0/-20 L/s, will be drawn from the room into the Isolator and Safety Cabinets and exhausted via a flexible duct (Supplier to install) to a ceiling spigot (105 mm) and onwards to a building a extract fan. The exhaust pressure at the outlet of the Isolator and Safety Cabinets must be 0 Pa ± 50 Pa. When the Isolator and Safety Cabinets is shut down or during the gassing phases of a VHP cycle, the Isolator and Safety Cabinets controls must open an automatic damper to divert directly to exhaust the same quantity of room air as is normally lost via the Isolator and Safety Cabinets.
DV
Required
IV
N.A.
OV
Required
All air fed and recirculated to the internal space of the Isolator and Safety Cabinets chamber and Transfer Hatch must be terminal HEPA filtered, using H14 grade filters. Inlet and recirculated air must be pre-filtered to prolong the life of the terminal HEPA filters.
DV
Required
IV
N.A.
OV
Required
DV
Required
IV
Required
Double exhaust HEPA filters are to be fitted to the Isolator and Safety Cabinets, but safe change of the primary exhaust filter is not required.
Sign / Date
Client: Project: Title:
A2.5.5.
A2.5.6.
A2.5.7.
A2.5.8.
A2.6
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
23 of 31
Test ports must be fitted for independent testing of all HEPA filters and their seals. This means the provision of test aerosol inlet points, aerosol challenge sampling points (e.g. in plenum chambers) and downstream sampling points.
Automatic shut-off valves must be provided to permit leak testing by pressure decay. These valves must be fitted ahead of the inlet HEPA filters and after the exhaust HEPA filters.
The air handling unit must be mounted integrally above, below or behind the Isolator and Safety Cabinets chamber, within the room.
The ventilation system of the Transfer Hatch must be compatible with alcohol spraying of process equipment and product containers which are placed in it.
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
Isolator and Safety Cabinets Sterilisation Requirement
A2.6.1.
A2.6.2.
A2.6.3.
Fulfilment
The Isolator and Safety Cabinets and built-in equipment must be engineered for automatic sterilisation by VHP treatment. Rotating or static gas distribution nozzles and stirring fans must be installed in the process chamber and hatch as required by the VHP System supplier. It must be possible to completely seal the Isolator and Safety Cabinets and/or Transfer Hatch from the room during sterilisation.
DV
Required
IV
Required
OV
Required
The Isolator and Safety Cabinets must have a VHP inlet and a VHP outlet port. Additionally, signal ports and gas sampling ports must be fitted to suit the VHP System. The gas inlet and outlet ports must be configured so that the (heavy) VHP hoses do not impart high bending moments on the ports.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
N.A.
OV
Required
The Isolator and Safety Cabinets must control the VHP sterilisation sequence. Therefore the Isolator and Safety Cabinets controller must first check that an ‘exhaust fan healthy’ signal is being received from the BMS. If this is not present, the Isolator and Safety Cabinets controller must stop and alarm. If the exhaust fan is OK, the Isolator and Safety Cabinets controller must send a ‘start’ signal to the VHP Generator (once a successful leak test has been completed), stop its fans and shut its isolation valves. The Isolator and Safety Cabinets controller then waits for an ‘aeration’ signal from the VHP Generator, at which point it must restart its fans and aerate the enclosure to finish the cycle. Finally, the Isolator and Safety Cabinets controller then waits for a “successful cycle completion” signal from the VHP Generator and then reverts to “Normal Operation”. Furthermore, the Isolator and Safety Cabinets must send signals to the EMS to close its particle counter/vacuum valves during VHP sterilisation and suspend particle counting.
Sign / Date
Client: Project: Title:
A2.6.4.
A2.6.5.
A2.6.6.
A2.6.7.
A2.6.8.
A2.6.9.
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
24 of 31
All valves which must be operated before, during or after a VHP sterilisation cycle must be automated.
DV
Required
IV
Required
OV
Required
DV
Required
IV
Required
OV
N.A.
Prior to an aseptic process batch it must be possible to place the necessary items, typically listed in A2.1.2, in the Isolator and Safety Cabinets and carry out a VHP sterilisation cycle (from start to completion of aeration) in approximately 90 minutes. In this context sterilisation is defined as a minimum of a 6-log reduction of spore forming microorganisms.
DV
Required
IV
N.A.
OV
Required (CGD)
It must be possible to VHP sterilise the Transfer Hatch independently from the process chamber, whist carrying out process operations in the chamber (Zero VHP leak in the chamber can be tolerated). The total VHP sterilisation cycle time must be less than 60 minutes.
DV
Required
IV
N.A
OV
Required (GCD)
It is proposed that Geobacillus stearothermophilus (ATCC # 12980) will be used as the test organism, prepared on proprietary biological indicator (BI) strips The Supplier must demonstrate equivalence of Geobacillus stearothermophilus (ATCC # 12980) to typical viruses that may be processed in the suite.
DV
Required
IV
N.A.
OV
Required (CGD)
A typical Isolator and Safety Cabinets and/or Hatch sterilisation sequence must be carried out as follows: Operator prepares load in Isolator and Safety Cabinets and/or Hatch. Operator moves VHP Generator to the Isolator and Safety Cabinets and connects gas hoses, sample tube and communications cables Operator plugs in VHP Generator to the mains and loads it with H2O2 solution. Operator places VHP Generator in run mode Operator selects gassing cycle (if there are different cycles validated for different loads) and initiates the gassing cycle at the Isolator and Safety Cabinets HMI. Isolator and Safety Cabinets controller sends signals to the EMS to indicate that it is gassing Isolator and Safety Cabinets controller controls the gassing cycle and aerates the enclosure at the end of the sterilisation period Isolator and Safety Cabinets controller indicates a successful cycle and goes into normal operation mode (sends signal to EMS to indicate normal operation) Operator stops the VHP Generator and removes the printout for batch records Operator disconnects hoses and communication cables and returns VHP Generator to its storage position Operator may take a manual air sample in the enclosure to confirm < 1ppm H2O2.
DV
Required
IV
N.A.
OV
Required (CGD)
Glove hangers must be supplied to hold up sleeves during VHP sterilisation.
Client: Project: Title:
A2.7
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
25 of 31
VHP Generator Operation and Performance Requirement
A2.7.1.
A2.7.2.
A2.7.3.
A minimum total of one mobile VHP Generator must be supplied to produce a stream of Hydrogen Peroxide Vapour in conditioned air (“gas”) to match the stated sterilisation requirements of the Isolators.
Mobile VHP Generators must be used to sterilise both Isolators and Safety Cabinet.
Mobile VHP Generators (if chosen) will be used to sterilise the following rooms and suites of rooms;
A2.7.4.
A2.7.5.
A2.7.6.
A VHP Generator must draw air from the room in which it is located.
A VHP Generator must produce concentrations of hydrogen peroxide and vapour temperatures and H202humidities within their set-point ranges.
The VHP Generators must produce the required environmental conditions and hydrogen peroxide vapour at a sufficient rate so that the total Isolator sterilisation cycle times stated in Section A2.6 If a VHP Generator alone cannot achieve the required cycle time then the following equipment must be included if required Catalytic H2O2 destruction units. Such units may be included in the VHP Generator cabinet or be separate mobile or fixed units incorporating appropriate circulation or exhaust fans.
A2.7.7.
A2.7.8.
1.18 – Viral Vectors 122m³ room volume 1.20 – Cytotoxics 97m³ room volume 1.33 – GMP Simulation – Grade D 200m³ room volume 1.34 – GMP Simulation – Grade C 144m³ room volume
Fulfilment DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
Required.
DV
Required
IV
N.A
OV
Required
DV
Required
IV
N.A
OV
Required
DV
Required
IV
Required
OV
N.A.
DV
Required
Separate distribution fans if appropriate.
The VHP Generators must use 30% H2O2 solution to produce VHP.
The VHP Generators must control the cycle so that the cycle completion point is when there is a concentration of
Sign / Date
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
26 of 31
less than 1ppm H2O2 in the enclosure being sterilised.
A2.8
IV
N.A
OV
Required
Cleanroom Sterilisation Requirement (applies to all VHP Generators unless specifically noted)
A2.8.1.
A2.8.2.
A2.8.3.
A2.8.4.
Fulfilment DV
N.A
IV
N.A
OV
N.A.
The following rooms may be gassed using the vHP • 1.18 – Viral Vectors 122m³ room volume 20 air changes per hour • 1.20 – Cytotoxics 97m³ room volume 20 air changes per hour • 1.33 – GMP Simulation – Grade D 200m³ room volume 20 air changes per hour • 1.34 – GMP Simulation – Grade C 144m³ room volume 30 air changes per hour The vHP Generator will be placed in room during gassing. This operation will be carried out on an occasional basis, i.e. once or twice a year, but may have to be done in an ‘emergency’ following a major spill or other incident.
DV
Required
IV
N.A
OV
Required (GCD)
It must be possible to VHP sterilise any one of the occasionally gassed rooms in a total cycle time of approximately 8 hours
DV
Required
IV
N.A
OV
Required
DV
Required
IV
N.A
OV
Required (GCD)
Isolator VHP sterilisation will not take place at the same time as room VHP sterilisation.
A typical cleanroom sterilisation sequence must be carried out as follows: Operator places VHP Generator in the room to be gassed, in the validated position (previously determined during room gassing cycle development), loads it with H2O2 solution and plugs it into the mains. Operator props open inner doors to any Pass Through Hatches in the room(s) and props open any doors to adjoining rooms to be gassed. Operator assembles the room gassing nozzle and connects the gas hose between the VHP Generator and it Operator connects the communications cable from the VHP Generator to the gassing socket in the room wall. Operator places VHP Generator in run mode. Operator checks rooms for personnel, leaves the room and tapes up all the outer doors and any other known air transfer paths such as transfer grilles or spool pieces. Operator posts warning notices. Operator connects the remote controller to power and to the gassing wall socket in the safe room outside the room(s) to be gassed. Operator selects the validated gassing cycle for the room(s) to sterilised and initiates the gassing cycle. Remote controller sends a signal to the EMS to indicate that it is gassing the rooms Remote controller sends a signal to the BMS to request that inlet and exhaust dampers are shut to the rooms Remote controller waits for a signal from the BMS to confirm that the requested inlet and exhaust dampers
Sign / Date
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
A2.8.5.
A2.8.6.
A2.9
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
27 of 31
are shut. Remote controller starts the VHP Generator and monitors the gassing cycle. At the end of the sterilisation period, the remote controller sends a signal to the BMS to request aeration (i.e. opening the inlet and exhaust dampers for once through aeration of the room(s). At the end of aeration, the remote controller indicates a successful cycle and sends a signal to EMS to indicate normal operation. Operator takes a manual air sample in the room to confirm < 1ppm H2O2. If safe, operator removes tape from outer door, enters room, stops the VHP Generator and removes the printout for batch records and dismantles the gassing equipment and returns it and the VHP Generator to storage.
In order to facilitate room VHP sterilisation, the Supplier must provide a communications wiring detailed design to the Main Contractor and free issue communications sockets, so that the Main Contractor may install the necessary wiring between the communications sockets in the rooms to be gassed, the communications sockets in the ‘safe’ rooms and the BMS and EMS The Supplier must label all communications sockets in the walls.
DV
Required
IV
Required
OV
N.A
It is proposed that Geobacillus stearothermophilus (ATCC # 12980) will be used as the test organism, prepared on proprietary biological indicator (BI) strips For rooms S21 to S26 the Supplier must demonstrate equivalence of Geobacillus stearothermophilus (ATCC # 12980) to typical viruses being processed in the suite.
DV
Required
IV
N.A
OV
Required (GCD)
VHP Generator Controls Requirement (applies to all VHP Generators unless specifically noted)
A2.9.1.
A2.9.2.
A2.9.3.
A2.9.4.
The control system of the VHP Generator must consist of a PLC with a fixed and a remote Human-Machine Interfaces (HMI).
The fixed HMI must comprise a membrane keypad or touchscreen, an alphanumeric display and a printer. The fixed HMI must be integrated within the VHP Generator cabinet.
The HMI must be used to initiate and monitor fully automated VHP sterilisation cycles in an Isolator
The remote HMI must be capable of communicating with the BMS and EMS, via a communication cable ‘gassing’ sockets located in each ‘safe’ room immediately outside the room or suite of rooms to be gassed. The remote HMI must be capable of sending a signal to the BMS and EMS which identifies the room(s) being gassed. The remote HMI must be capable of communicating with any VHP generator via communications cables and a ‘bulkhead’ type socket in the wall between the ‘safe’ room and the room being gassed where the VHP Generator is located.
Fulfilment DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A
DV
Required
IV
N.A
OV
Required
DV
Required
IV
N.A
OV
Required
Sign / Date
Client: Project: Title:
A2.9.5.
A2.9.6.
A2.9.7.
A2.9.8.
A2.9.9.
A2.9.10.
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
28 of 31
The VHP Generators must be equipped with the following instruments/sensors H2O2 solution weight or volume
H2O2 vapour concentration
H2O2 vapour temperature
Data viewable on the alphanumeric display must include:
DV
Required
IV
Required
OV
N.A
DV
Required
Alarms
IV
Required
Machine status (ready, in-use, not ready)
OV
N.A
H2O2 solution weight or volume
H2O2 vapour concentration
H2O2 vapour temperature DV
Required
The printed cycle report must include:
Batch No.
IV
Required
Operator ID
OV
Required
Equipment Treated (Tag. No.)
Time and date start cycle
Time and date finish cycle
Settings used for the cycle
H2O2 solution weight or volume used
H2O2 vapour concentration and temperature at phase transitions, with time
Alarms during the cycle, with time
Summary, i.e. “Cycle Successful” or “Cycle Aborted” DV
Required
IV
N.A
OV
Required
DV
Required
The HMI system must be password protected at least three levels Operator,
Supervisor,
Administrator/Engineer/Validator
The controller must provide the following alarm systems.
Out of H2O2 solution
IV
Required
Gas concentration or temperature out of specification.
OV
Required
Catalytic converter out of specification (if included). DV
Required
IV
Required
OV
Required
The controller must provide the following interlock systems, which must be both hardware and software implemented.
VHP generation must not start if Isolator leak test fails
VHP generation must not start if room dampers are not closed
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
29 of 31
VHP generator goes to aeration if the “Abort” button is pressed.
A2.9.11. The required range and accuracy of the instrumentation is given in the table below.
DV
Required
IV
Required
OV
N.A.
A2.9.12. Settable high and low alarms must be fitted to all analogue instruments. Alarms must be annunciated by audible and visible means. Alarms must be latched, i.e. alarms can only be cleared by manual intervention once the excursion has been corrected.
DV
Required
IV
Required
OV
Required
A2.9.13. Both the fixed and remote HMI’s must have an “Abort” button, which has the function of stopping a gassing sequence and driving the Isolator or room HVAC to full aeration.
DV
Required
IV
Required
OV
Required
DV
Required
IV
Required
OV
N.A
DV
Required
IV
Required
OV
Required
Instrument
Range
Accuracy
Precision
Weight/Volume
0 – 250 g/mL
+ 0.1 g/mL
0.1 g/mL
H2O2 Concentration (low range)
0 – 5 ppm
+ 0.5 ppm
0.1 ppm
Temperature
0 – 100 oC
+ 1 oC
1 oC
A2.9.14. All instruments must be clearly labelled in English with their function
A2.9.15
If the selected control system falls within the guidance of Annex 11 (Computerised Systems) of the EU GMP regulations, then password protection must comply with sections 8 and 10 of Annex 11 of the EU GMP regulations. This states that all actions carried out under password control must be logged, with the identity of the person initiating the actions.
A2.10 VHP Generator Construction Requirement A2.10.1. The VHP Generator’s (if mobile rather than built in) overall footprint must not exceed 700 mm x 900mm.
A2.10.2. Materials and design of construction must enable easy and effective cleaning to be performed. All functional parts of the VHP Generator must be enclosed in a single cabinet, with secure access doors for maintenance. All items requiring observation, maintenance or calibration must be located so as to allow easy and safe access. The external finish of the machine cabinet must be powder coated steel or equivalent. The Mobile VHP Generator must be mounted on four cleanroom type castors, at least two of which must be lockable. A2.10.3. The HMI for the VHP Generator must be ergonomically sited and must be between 800 mm and 1200 mm above floor level.
Fulfilment DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
OV
N.A.
DV
Required
IV
Required
Sign / Date
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
30 of 31
OV
N.A
A2.10.4. The mobile VHP Generator be supplied with two “gas” hoses; one for supply to the Isolator and the other for return from the Isolator. All “gas” hoses shall be armoured platinum crosslinked silicone tubing with ends to match the nozzles on the isolator/ and Room Nozzle
DV
Required
IV
Required
OV
N.A
A2.10.5. Each major component or sub-assembly in the system must be identified with a permanently fixed tag, the tag having an engraved or embossed number corresponding to its identification on the P&ID.
1
Required
IV
Required
OV
N.A
Client: Project: Title:
Centre for Process Innovation (CPI) National Biologics Manufacturing Centre (NBMC) URS – Isolators and Safety Cabinets
Validation Doc Number:
na
Validation issue:
na
Version:
2.0
Page:
31 of 31
APPENDIX 3 –3-WAY VALVE OPERATION
Exhaust stack tp atmosphere
1 –Exhaust Stack – Normal and post vHP
From Room
From room Isolator
vHP Generator
Exhaust stack to atmosphere
2 – Exhaust Stack – During vHP Gassing
From Room
From room Isolator
vHP Generator
View more...
Comments
